Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Background: and Purpose Intravenous tenecteplase (TNK) efficacy has not been well demonstrated in acute ischemic stroke (AIS) beyond 4.5 hours after onset. This study aimed to determine the effect of intravenous TNK for AIS within 4.5 to 24 hours of onset. Methods: In this pilot trial, eligible AIS patients with diffusion-weighted imaging (DWI)-fluid attenuated inversion recovery (FLAIR) mismatch were randomly allocated to intravenous TNK (0.25 mg/kg) or standard care within 4.5–24 hours of onset. The primary endpoint was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score of 0–1). The primary safety endpoint was symptomatic intracranial hemorrhage (sICH). Results: Of the randomly assigned 80 patients, the primary endpoint occurred in 52.5% (21/40) of TNK group and 50.0% (20/40) of control group, with no significant difference (unadjusted odds ratio, 1.11; 95% confidence interval 0.46–2.66; P=0.82). More early neurological improvement occurred in TNK group than in control group (11 vs. 3, P=0.03), but no significant differences were found in other secondary endpoints, such as mRS 0–2 at 90 days, shift analysis of mRS at 90 days, and change in National Institutes of Health Stroke Scale score at 24 hours and 7 days. There were no cases of sICH in this trial; however, asymptomatic intracranial hemorrhage occurred in 3 of the 40 patients (7.5%) in the TNK group. Conclusion This phase 2, randomized, multicenter study suggests that intravenous TNK within 4.5–24 hours of onset may be safe and feasible in AIS patients with a DWI-FLAIR mismatch.

Objective Observe the effect of Liuwei Anshen Capsule on sleep improvement of aged sleep deprivation zebrafish model.Methods Sixty 18-month-old female zebrafish were randomly divided into blank group,model group,Liuwei Anshen group,and melatonin group.The zebrafish in the blank group were raised under normal lighting conditions,and the other three groups were constructed with continuous lighting for 3 days.Zebrafish in Liuwei Anshen group were treated with Liuwei Anshen capsule water solution 0.000 50 mg·mL-1 for 3 days on the basis of model group,and zebrafish in melatonin group were treated with melatonin aqueous solution 0.2 mg·mL-1 on the basis of model group for 3 days.After 3 days,the zebrafish behavior system was used to detect the resting time of zebrafish in each group.qRT-PCR method was used to detect cyclin 1a(per1a),cyclin2(per2),circadian motor output cycle 1a(clock1a),cryptochrome 1b(cry1b),and 5-hydroxyindoleacetic acid(5-htiaa)in each group of zebrafish and follicle-stimulating hormone beta(fshβ)gene expression levels.Western blot was used to detect the expression levels of estrogen receptorα(Esrα),Fshβand luteinizing hormone(Lh)in zebrafish in each group.HE staining was used to observe the ovary of zebrafish in each group.Results Compared with the zebrafish in the blank group,the resting time of the zebrafish in the model group decreased significantly(P<0.01)during the 24 hours of observation.After the intervention of Liuwei Anshen Capsule and melatonin,the resting time of the zebrafish was significantly increased.(P<0.01).Compared with the zebrafish in the blank group,the mRNA expressions of zebrafish circadian clock genes per1a,per2,clock1a,cry1b,5-htiaa,and fshβ all showed a downward trend after sleep deprivation(P<0.05,P<0.01).After the intervention of Liuwei Anshen Capsules,the mRNA expressions of per1,clock1a,cry1b,5-htiaa and fshβ were all up-regulated(P<0.05,P<0.01).Compared with the zebrafish in the blank group,the protein expressions of Esrα and Lh in the zebrafish of the model group were up-regulated(P<0.05),the expression of Fshβ protein was down-regulated(P<0.05),after the intervention of Liuwei Anshen Capsules,the above proteins did not change significantly.The ovarian tissue cells of the zebrafish in the blank group had normal morphology and a large number of primary oocytes,while the ovarian tissue cells of the zebrafish in the model group were damaged in morphology and the number of primary oocytes decreased,after the intervention of Liuwei Anshen Capsule and melatonin,the cell morphology of zebrafish ovarian tissue was still damaged to varying degrees,but the whole was relatively intact,and the number of primary oocytes increased.Conclusion The insomnia of aged zebrafish may be caused by multiple factors.Liuwei Anshen capsule has significant effects on estrogen level of rhythm gene and ovarian function of sleep-deprived aged zebrafish.

Objective To investigate the clinical efficacy of low-dose plasma exchange (PE) combined with artificial liver in the treatment of acute-on-chronic liver failure (ACLF) and its effect on mortality rate after stratification. Methods A total of 272 ACLF patients who were admitted to Department of Infection and Hepatology, The First Affiliated Hospital of Kunming Medical University, from January 2018 to December 2020 were enrolled and divided into low-dose PE+double plasma molecular absorption system (DPMAS)/hemoperfusion (HP) group ( n =190) and medical treatment group( n =82). Laboratory markers were collected before and after treatment, and clinical outcome was compared between the two groups; stratified analysis (early stage, early-middle stage, late stage or types A, B, C) was performed for the two groups according to Diagnostic and treatment guidelines for liver failure (2018 edition), and all patients were followed up to observe general status and death at 12 weeks (short-term) and 48 weeks (long-term) after discharge. The independent samples t -test was used for comparison of normally distributed continuous data between two groups, and the paired samples t -test was used for comparison before and after treatment; the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Wilcoxon test was used for comparison before and after treatment; the chi-square test was used for comparison of categorical data between groups. Results Both low-dose PE combined with DPMAS/HP and medical treatment alone could reduce the levels of alanine aminotransferase (ALT), aspartate aminotransferase, total bilirubin (TBil), and blood ammonia and increase the level of albumin (Alb), and both groups had significant changes in these indices after treatment (all P < 0.05). Compared with medical treatment alone, low-dose PE combined with DPMAS/HP better reduced ALT, TBil, and blood ammonia and improved Alb, with significant changes in these indices after treatment (all P < 0.05). Low-dose PE combined with DPMAS/HP could significantly reduce bile acid, international normalized ratio, neutrophil-lymphocyte ratio, and MELD score and increase platelet-to-white blood cell ratio (all P < 0.05), while medical treatment alone could not improve the above indices (all P > 0.05). Compared with medical treatment alone, low-dose PE combined with DPMAS/HP could reduce the short-term mortality rate of ACLF patients, especially the short-term mortality rate of ACLF patients with early-stage, early-middle-stage or type A ACLF, and there were significant differences between the two groups (all P < 0.05). In the low-dose PE+DPMAS/HP group, the patients with early-stage ACLF had significantly lower short- and long-term mortality rates than those with late-stage ACLF, and the patients with type A ACLF had significantly lower short- and long-term mortality rates than those with type C ACLF (all P < 0.05). Conclusion Low-dose PE combined with DPMAS/HP has good clinical efficacy and can effectively reduce the short-term mortality rate of ACLF, especially the short-term mortality rate of patients with early-stage, early-middle-stage, or type A ACLF.

Objective:To understand the epidemiologic characteristics of fall in people aged 60 years and above in China from 2015 to 2018, and provide basis for the prevention of fall in old people and the development of related policies.Methods:Descriptive analysis was conducted on general information, injury occurrence information and injury clinical characteristics of fall cases in people aged 60 years and above by using the data from Chinese National Injury Surveillance System(NISS).Results:A total of 205 670 fall cases were reported to NISS from 2015 to 2018 with the male to female ratio of 1.37. Falls mainly occurred during 10:00-10:59 am (11.91%). The top three places where fall might occur were home (56.41%), road (17.24%) and public residence (14.36%). Leisure activity(37.56%), housework (24.20%) and walk (15.07%) were top three activities in which fall occurred. Bruise/scrape (42.17%), fracture (31.79%) and sprain/strain (14.62%) were the major injuries. The most common body parts involved were low limbs (31.38%), head (22.46%) and truncus(20.71%). Moderate and severe injuries accounted for 37.21% of all cases, and 22.49% of the elderly seeking medical care due to fall required hospitalization.Conclusions:The number of fall in people aged 60 years and above increased from 2015 to 2018. The elderly is a key population in the prevention and control of fall.

Objective:To investigate the incidence of injuries among children aged 0-17 years from 28 counties in six provinces.Methods:According to the earlier study on data in different local areas and the current work plan, we selected the survey objects for a general survey on child injury prevalence in the last 12 months. The subjects included guardians of children who did not attend kindergartens, children from kindergartens, and primary school grades 1-3. Children from grades 4-6 primary school, junior high school, and senior high school were also included.Results:The overall rate of injured children was 4.83%, with the incidence of injuries as 5.75% in the last 12 months before the survey. Both the rate of injured children and incidence of injuries were higher in boys than that in girls. Children whose primary caregivers were relatives, grandparents, minors, or with an education level below the primary school had a relatively higher rate of both injured children and incidence of injuries. The first cause of child injury was fall. The time of child injury was mainly from June to October, mainly at home, with the main activity as playing. The significant injuries in children were contusion and abrasion, and the main parts injured were lower limbs, upper limbs, and head. Most of the injuries were cured, and the primary treatment was outpatient and emergency treatment.Conclusions:Boys and children whose parents can not take care of are the priority population for child injury prevention and control. Targeted prevention and control measures should be implemented according to the characteristics of injuries among children of different ages.

Objective:To understand the epidemiological characteristic and influencing factors of animal injuries among children from 28 counties/districts in 6 provinces of China to provide evidence for formulating related prevention measures and strategies.Methods:Data was obtained from 'Children injury prevention project, 2016-2020'. Variables on the characteristics, including incidence, locations, related activities, time, and outcomes among children, were described. The negative binomial regression model analyzed animal injury frequency influencing factors.Results:There were 107 029 boys and 97 599 girls, with a gender ratio of 1.10, among the 204 628 children aged 0-17 in 28 counties/districts in 6 provinces of China. Per-person and per-time incidence rates of animal injuries were 0.70% and 0.72%, both higher in boys than in girls. Animal injuries among children mainly occurred in home (73.20%), road/street (7.51%), and open space of community/village (6.77%), during playing (63.15%), with the peak time between 12:01-18:00 (45.03%). Upper limbs (47.89%), lower limbs (35.31%), and head (8.44%) were the most injured body parts. Outpatient or emergency treatment (85.19%) had been carried out. The negative binomial regression showed that sex, grade, guardian educational level, urban or rural, and daily communication between guardians and children as influencing factors in the frequency of animal injuries among children.Conclusions:Special attention should be given to boys, at home, in projects on animal injury prevention and control. There were many influencing factors of animal injury frequency. Knowledge of injury prevention should be popularized to children and guardians. Related comprehensive intervention should be developed in families, schools, and social settings.

Objective:To investigate the incidence of traffic injuries among children aged 0-17 years in 28 counties of 6 provinces and to provide prevention suggestions.Methods:Using the general survey method, a questionnaire survey was conducted on the road traffic injuries of children in 28 counties of 6 provinces in 2017.Results:A total of 204 628 students were surveyed, 908 of whom had experiences of road traffic injuries. Road traffic injuries were 0.44% among children in 28 counties of 6 provinces in China and 0.94% among children who did not attend kindergartens. July is a high incidence period of road traffic injuries among children (12.92%). When children suffer from road traffic injuries, the first three activities were playing (21.61%), riding an electric bicycle (20.40%), walking (20.07%). Most injuries appeared as contusion/abrasion, accounting for 42.26% of the total cases. The injured parts were mainly lower limbs, upper limbs, and heads, accounting for 38.85%, 23.29%, and 20.20%. Most children with road traffic injuries recovered after related treatments, accounting for 85.43% of all cases. The median length of hospital stay of children with road traffic injuries was seven days, and the median expense in hospitals was 3 000 Yuan (RMB).Conclusions:The incidence of road traffic injuries among males appeared higher than females, and the children who did not attend the kindergartens were the highest. During playing, riding an electric bicycle and walking were the top three activities prone to road traffic injuries.

Objective: To analyze the characteristics distribution of falls among students aged 6-17 in 2018, and to provide data support for preventing falls among students and formulating the corresponding policies. Methods: Data of falls among students aged 6-17 in China in 2018 were collected from the the National Injury Surveillance System (NISS) for analyzing its demographic characteristics, injury occurrence and clinical traits of falling. Results: In total, 42 735 cases of fall aged 6-17 were collected from the NISS in China in 2018, which accounted for 54.03% of all cases, with a sex ratio of 2.34∶1, the proportion of students aged 6-11 was the highest(53.78%). The proportion of falls from March to June was the highest(42.12%), and the peak time when falls occurred was forenoon 10:00-10:59(8.40%). School and school-related area(40.40%), home(18.96%) and public residential institution (15.35%) were the sites where falls mainly occurred. The top three activities when falls occurred were leisure activities(47.41%), sports activities(23.90%) and walking(9.77%). Bruise/scrape(54.49%), sprain/strain(21.98%) and fracture(12.69%) were the major nature of injury. The most common body parts falls involved were lower limbs(34.71%), head(29.85%) and upper limbs(25.10%). The injury of falling was mainly characterized by mild ones(83.44%). Conclusion There were more cases of falls on students aged 6-17 from the NISS in China in 2018, mainly males. The epidemiological characteristics were relatively variable, so targeted prevention program of falls should be conducted.

Objective: To understand the epidemiologic characteristics of injury among children aged 0-5 years in 2018, and to provide evidence for prevention and control measures of injury in children. Methods: Data of injury in children aged 0-5 years in China in 2018 were collected from National Injury Surveillance System (NISS) for the descriptive epidemiologic analysis. Results: A total of 74 355 injury cases were reported in children aged 0-5 years in 2018, with the gender ratio of 0.66, in which 98.13% were unintentional injuries. The top three causes of injury were falls (56.76%), blunt injuries (9.80%) and animal related injuries (7.81%). Injuries mainly occurred during 17:00—20:59 (32.09%) and 10:00—11:59 (13.95%). The top three places where injuries might occur were home (65.70%), public residence (13.06%), highway/street (10.94%). Recreational activities (64.21%), basic life activities (16.93%) and walking (5.66%) were the main activities when injuries occurred. Of all injury cases, most were mild, while 13.73% of cases were moderate or severe. Head, upper limb and lower limb were main injuries sites, which accounted for 49.44%, 28.59% and 11.70% of all cases respectively. Conclusion Injury is an important cause for children aged 0-5 years to go to the outpatient/emergency department for treatment, indicating that the prevention of injury in such age group should be strengthened. It is recommended to further improve the data collection on child injury in order to provide more evidence for child injury intervention.